Abstract We have developed a novel single-frame x-ray tomosynthesis (SFXT) imaging architecture that can produce 30 tomosynthesis volumes per second. Compared to conventional tomosynthesis, SFXT has a reduced field of view and projection count but 10 to 100 times higher temporal resolution. This dramatic increase in speed has the potential to open new clinical applications. The device utilizes standard components and is simple in design compared to CT or MRI. We will build a prototype system, image both stationary and moving phantoms, and conduct a pilot study to image swine during normal respiratory and cardiac motion. We will further evaluate the utilization of SFXT in two specific applications. First, in radiation oncology, SFXT could guide the treatment of lung stereotactic body radiation therapy (SBRT). By providing real-time feedback of the lung tumor location, SFXT could enable safer ablation of central lung tumors with reduced incidence of radiation pneumonitis or damage to the central airways, great vessels, or esophagus. Second, in the detection of cardiovascular disease, SFXT could visualize calcium deposits in the coronary arteries. This has previously been achieved using CT, but SFXT would provide the cost and radiation exposure profile necessary for calcium scoring to become a routine tool in the personalized management of cardiovascular health. Still other, undiscovered applications may be enabled by the high temporal resolution of SFXT.